Substituted 2-imino-5-arylidenethiazolidin-4-one inhibitors of bacterial type III secretion.
Diverse species of pathogenic Gram-negative bacteria use secretion systems to export a variety of protein toxins and virulence factors that help establish and maintain infection. Disruption of such secretion systems is a potentially effective therapeutic strategy. We developed a high-throughput screen and identified a tris-aryl substituted 2-imino-5-arylidenethiazolidin-4-one, compound 1, as an inhibitor of the type III secretion system. Expansion of this chemotype enabled us to define the essential pharmacophore for type III secretion inhibition by this structural class. A synthetic diversity set helped us identify N-3 as the most permissive locus and led to the design of a panel of novel N-3-dipeptide-modified congeners with improved activity and physiochemical properties. We now report on the synthesis of these compounds, including a novel solid phase approach to the rapid generation of the dipeptide-thiazolidinone hybrids, and their in vitro characterization as inhibitors of type III secretion in Salmonella enterica serovar Typhimurium.
Kline
Toni
T
Departments of Genome Sciences, Microbiology, and Medicine, University of Washington, Seattle, Washington 98195, USA. klinet@u.washington.edu
Felise
Heather B
HB
Barry
Kathleen C
KC
Jackson
Stona R
SR
Nguyen
Hai V
HV
Miller
Samuel I
SI
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000378:metabolism* / Q000472:pathogenicity; D013237:Stereoisomerism; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D053778:Thiazolidines